Cancer-induced Weakness in Immune System May Be Key to HER2+ Breast Cancer Recurrence, and Prevention

Cancer-induced Weakness in Immune System May Be Key to HER2+ Breast Cancer Recurrence, and Prevention

T cells from patients whose breast cancer had recently recurred showed far weaker response to the HER2 receptor protein, compared with T cells from patients whose breast cancer had not recurred over a long period following treatment, according to a study published in JAMA Oncology (doi:10.1001/jamaoncol.2015.5482).

The study findings suggest that patients with HER2-positive breast cancer—an estimated 20% of the 260,000 invasive breast cancers diagnosed in the United States each year—might someday undergo immune status monitoring with blood tests before, during, and after treatment, allowing physicians the chance gauge the risk of recurrence, and possibly reduce that risk with therapies that boost anti-HER2 immunity.

Recurrence of HER2-positive breast cancer may be due to a specific and possibly cancer-induced weakness in the patient's immune system, a weakness that in principle could be corrected with a HER2-targeted vaccine.

"We know that it's not a fixed immune defect, because we have several clinical trials open where we're vaccinating people and can restore anti-HER2 responsivity," said Brian J. Czerniecki, MD, PhD, the Rhodes-Harrington Professor in Surgical Oncology at the University of Pennsylvania and the co-director of the Rena Rowan Breast Center at Penn Abramson Cancer Center in Philadelphia, and senior author of the study.

Czerniecki and colleagues have been investigating the role of the immune system in breast cancer, and the potential of cancer vaccines, for most of the past 2 decades. Their most recent research has focused on the T-helper type 1, or Th1, immune response in cancer, in which helper T cells mobilize killer cells to attack cancer-related targets.

In this study, the research team isolated immune cells from 95 women with invasive HER2-positive breast cancer and analyzed the cells' ability to mount a Th1 response against the HER2 growth factor receptor protein. HER2-positive breast cancer cells overexpress the HER2 receptor to help drive their rapid proliferation.

The team found that, by a standard measure, the cells from women with recently recurrent cancer that had not yet been re-treated had only about a tenth of the anti-HER2 responsivity compared with that seen in women whose HER2+ breast cancer had not recurred for at least 2 years following treatment.

Looking at anti-HER2 responsivity across all the patients, the researchers found that patients with the least amount of responsivity had experienced only 47 disease-free months after treatment, on average, compared with 113 disease-free months for the patients with the highest responsivity.

The low anti-HER2 responsivity seen in the women with recurrent cancer was not part of a broader immune suppression. "We detected no other immune deficit; just the deficit in the anti-HER2 response," Czerniecki said.

How patients lose their anti-HER2 responsivity during the formation and growth of a HER2-positive tumor is not yet clear.

"The thinking is that the patient's anti-HER2 T cells somehow become exhausted and die or otherwise stop responding," Czerniecki said. "We're trying to determine the mechanism, but we already know that we can 'fill the tank' with vaccines to restore that specific responsivity to HER2."

In addition to conducting ongoing mechanistic studies and vaccine trials, Czerniecki's team hopes to confirm the association between anti-HER2 responsivity and cancer recurrence risk in larger clinical trials that would track patients' immune status over time.